Dr Calais on Sequencing PSMA-Targeted Therapy With PARP Inhibitors and Chemotherapy in Prostate Cancer

“There is a lot about patient choice in terms of toxicity profile, [adverse] effect profile, a lot of conversation with the patient on what we should expect.”

Jeremie Calais, MD, PhD, a professor of nuclear medicine and theranostics at Gustave Roussy and Université Paris-Saclay and an adjunct professor at UCLA Health, discussed how molecular eligibility, disease aggressiveness, and patient preferences informed sequencing of prostate-specific membrane antigen (PSMA)–targeted radioligand therapy relative to PARP inhibitors and chemotherapy for patients with prostate cancer.

For patients eligible for PARP inhibition on the basis of BRCA mutations or other homologous recombination repair alterations, Calais favored using a PARP inhibitor before PSMA-targeted treatment. He cited the evidence supporting benefit in eligible patients and explained that PSMA expression would generally remain available as a target, even if disease progressed during the preceding PARP inhibitor treatment.

However, Calais acknowledged that prospective trials have not directly established which of these treatment sequences is superior. He framed his preference as an interpretation of the available evidence and favored reserving lutetium-based PSMA therapy for subsequent treatment in patients with an appropriate molecularly targeted option.

When considering radioligand therapy relative to chemotherapy, Calais placed greater emphasis on discussions with patients. He highlighted the importance of comparing toxicity and adverse effect profiles, citing the need to explain what patients could expect from each approach. He indicated that individual preferences helped shape these decisions.

Disease aggressiveness represented another important distinction. Calais explained that the implications of administering PSMA-targeted treatment before or after chemotherapy could differ according to the clinical presentation. His discussion emphasized that results observed in one study population could not automatically define the best sequence for another.

Calais contrasted findings across studies involving different disease characteristics and control treatments. In discussing the phase 3 PSMAfore trial (NCT04689828), he suggested that lutetium-based PSMA therapy could be favored for patients in whom chemotherapy could reasonably be postponed, particularly those without highly aggressive disease.

Conversely, he expressed greater caution about prioritizing radioligand treatment in patients with very aggressive disease. He emphasized that the comparison with chemotherapy required attention to the population studied rather than assuming the same relative benefit across all patients.

Calais concluded that treatment sequencing should be individualized. His discussion brought together biomarker-directed eligibility, the continued availability of PSMA as a target, disease behavior, and patient preferences, while preserving the distinction between his clinical interpretation and evidence from a direct prospective sequencing comparison.